Endogenous glucocorticoids decrease skeletal angiogenesis, vascularity, hydration, and strength in aged mice

Abstract

SummaryAging or glucocorticoid excess decrease bone strength more than bone mass in humans and mice, but an explanation for this mismatch remains elusive. We report that aging in C57BL ⁄ 6 mice was associated with an increase in adrenal production of glucocorticoids as well as bone expression of 11b-hydroxysteroid dehydrogenase (11b-HSD) type 1, the enzyme that activates glucocorticoids. Aging also decreased the volume of the bone vasculature and solute transport from the peripheral circulation to the lacunar-canalicular system. The same changes were reproduced by pharmacologic hyperglucocorticoidism. Furthermore, mice in which osteoblasts and osteocytes were shielded from glucocorticoids via cell-specific transgenic expression of 11b-HSD type 2, the enzyme that inactivates glucocorticoids, were protected from the adverse effects of aging on osteoblast and osteocyte apoptosis, bone formation rate and microarchitecture, crystallinity, vasculature volume, interstitial fluid, and strength. In addition, glucocorticoids suppressed angiogenesis in fetal metatarsals and hypoxia inducible factor-1a transcription and vascular endothelial growth factor production in osteoblasts and osteocytes. These results, together with the evidence that dehydration of bone decreases strength, reveal that endogenous glucocorticoids increase skeletal fragility in old age as a result of cell autonomous effects on osteoblasts and osteocytes leading to interconnected decrements in bone angiogenesis, vasculature volume, and osteocyte-lacunar-canalicular fluid.

Suppression of Autophagy in Osteocytes Mimics Skeletal Aging

“…We have shown previously that blockade of glucocorticoid action on osteoblasts and osteocytes blunts the loss of bone mass and strength caused by aging in mice (50). We also noted in those studies that corticosterone levels in the circulation increase with age.…”

Tao-Hong-Si-Wu Decoction ameliorates steroid-induced avascular necrosis of the femoral head by regulating the HIF-1α pathway and cell apoptosis

“…The significance of HIF-1α is also evident from the fact that administration of ethyl 3,4-dihudroxybenzoate (EDHB) deters the progression of SANFH because it inhibits the functioning of HIF prolyl hydroxylase and it stabilizes HIF-1α expression (1,30,31). A target gene of HIF-1α, VEGF, also plays a major role in encouraging the angiogenesis-osteogenesis coupling process (32)(33)(34). VEGF improves angiogenesis by activating a variety of signal pathways.…”

Glucocorticoids and Tumor Necrosis Factor α Increase Oxidative Stress and Suppress Wnt Protein Signaling in Osteoblasts

“…Earlier work from our group and others has shown that an increase in endogenous GCs and inflammatory cytokines contributes to the age-associated loss of bone mass and strength (6,11). Moreover, administration of GCs or an endogenous rise in TNF␣ has been causally linked to increased osteoclast numbers, decreased osteoblast numbers, and bone loss (1,50).…”

“…We and others have shown that GCs or TNF␣ increase osteoblast and osteocyte apoptosis. Importantly, bone fragility induced by chronic GC excess is due, to a large extent, to increased osteocyte apoptosis and results from cell autonomous effects (6,56). In view of this evidence, we have searched here for a mechanism linking ROS to the pro-apoptotic actions of GCs and TNF␣.…”

“…However, the molecular mechanisms responsible for these deleterious effects remain unclear. Endogenous GC levels increase by 20 -50% with age in humans and mice (3)(4)(5)(6)(7) because of blunting of the GC feedback inhibition of ACTH (8) as well as increased bone expression of 11␤-hydroxysteroid dehydrogenase type 1, the enzyme that converts GCs from inactive to active moieties (6,9). TNF␣ is a critical mediator of skeletal damage in inflammatory arthritis (10,11).…”